Is CHRNA2 p.Arg422Ser (c.1266A>T) pathogenic?

CHRNA2 p.Arg422Ser (c.1266A>T) is classified Uncertain significance in CHRNA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-22). AlphaMissense: likely benign (0.1256); Absent from gnomAD v4.1; Associated with familial sleep-related hypermotor epilepsy.

What condition is associated with CHRNA2 p.Arg422Ser (c.1266A>T)?

CHRNA2 p.Arg422Ser (c.1266A>T) is associated with familial sleep-related hypermotor epilepsy (ClinVar).

How common is CHRNA2 p.Arg422Ser (c.1266A>T) in the general population?

CHRNA2 p.Arg422Ser (c.1266A>T) is absent from gnomAD v4.1 (gnomAD).

How is Sleep-related hypermotor epilepsy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHRNA2 p.Arg422Ser (c.1266A>T)?

AlphaMissense predicts likely benign (score 0.1256) — an in-silico prediction, not a clinical call.

CHRNA2 p.Arg422Ser

c.1266A>T · rs2132650884 · VCV1349848

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1256 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial sleep-related hypermotor epilepsy

Computational evidence

Protein change
AlphaMissense	0.1256	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.34	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.2	GERP -1.6
Regional constraint	o/e 1.05	unconstrained · MANE · 1,855 bp · p 0.38 · regional, not allelic
Overall
CADD	2.587	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHRNA2
Protein: p.Arg422Ser
Coding: c.1266A>T
MANE Select: NM_000742
dbSNP: rs2132650884
Type: single nucleotide variant
Location: chr8:27463177 (GRCh38)
Gene constraint: LOEUF 1.195 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.88 · 1 PDB

Full CHRNA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial sleep-related hypermotor epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Sleep-related hypermotor epilepsy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

CHRNA2 p.Arg422Gly Uncertain significance ★ ⚠ same residue
CHRNA2 c.1464+4C>T Uncertain significance ★★ same condition
CHRNA2 c.1464+5G>A Uncertain significance ★★ same condition
CHRNA2 c.294+1G>A Uncertain significance ★★ same condition
CHRNA2 c.294+5G>A Uncertain significance ★★ same condition
CHRNA2 c.449+3A>T Uncertain significance ★★ same condition
CHRNA2 c.73+4A>C Uncertain significance ★★ same condition
CHRNA2 p.Ala177Pro Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/chrna2-p-arg422ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown